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Controlled Human Hookworm Infection: Accelerating Human Hookworm Vaccine Development.

ABSTRACT: Background:Controlled human hookworm infection (CHHI) is a central component of a proposed hookworm vaccination-challenge model (HVCM) to test the efficacy of candidate vaccines. Critical to CHHI is the manufacture of Necator americanus infective larvae (NaL3) according to current Good Manufacturing Practice (cGMP) and the determination of an inoculum of NaL3 that is safe and reliably induces patent infection. Methods:cGMP-grade NaL3 were produced for a phase 1 trial in 20 healthy, hookworm-naïve adults in the United States, who received either 25 or 50 NaL3. Participants were monitored for 12-18 weeks postinfection for safety, tolerability, and patency of N. americanus infection. Results:Both NaL3 doses were well tolerated. Early manifestations of infection included pruritus, pain, and papulovesicular rash at the application site. Gastrointestinal symptoms and eosinophilia appeared after week 4 postinfection. The 50 NaL3 inoculum induced patent N. americanus infection in 90% of this dose group. Conclusions:The inoculum of 50 NaL3 was well tolerated and consistently induced patent N. americanus infection suitable for future HVCM trials. Clinical Trials Registration:NCT01940757.

SUBMITTER: Diemert D

PROVIDER: S-EPMC5952933 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Controlled Human Hookworm Infection: Accelerating Human Hookworm Vaccine Development.

Diemert David D Campbell Doreen D Brelsford Jill J Leasure Caitlyn C Li Guangzhao G Peng Jin J Zumer Maria M Younes Naji N Bottazzi Maria Elena ME Mejia Rojelio R Pritchard David I DI Hawdon John M JM Bethony Jeffrey M JM

Open forum infectious diseases 20180419 5

<h4>Background</h4>Controlled human hookworm infection (CHHI) is a central component of a proposed hookworm vaccination-challenge model (HVCM) to test the efficacy of candidate vaccines. Critical to CHHI is the manufacture of <i>Necator americanus</i> infective larvae (<i>Na</i>L3) according to current Good Manufacturing Practice (cGMP) and the determination of an inoculum of <i>Na</i>L3 that is safe and reliably induces patent infection.<h4>Methods</h4>cGMP-grade <i>Na</i>L3 were produced for a ...[more]

PMID: 29780848

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Project description:BackgroundThe Necator americanus hemoglobinase, aspartic protease-1 (Na-APR-1), facilitates the ability of adult hookworms to parasitize the intestine of their human hosts. A recombinant version of APR-1 protected laboratory animals against hookworm infection by inducing neutralizing antibodies that block the protein's enzymatic activity and thereby impair blood feeding. A catalytically inactive version of the wild-type hemoglobinase (Na-APR-1(M74)) was expressed by infiltrating Nicotiana benthamiana tobacco plants with an Agrobacterium tumefaciens strain engineered to express the vaccine antigen, which was adjuvanted with aluminum hydroxide adjuvant (Alhydrogel).MethodsAn open-label dose-escalation Phase 1 clinical trial was conducted in 40 healthy, hookworm-naïve adult volunteers in the United States. Participants received 30 or 100 µg of recombinant Na-APR-1(M74) with Alhydrogel or with Alhydrogel co-administered with one of two doses (2.5 or 5.0 µg) of an aqueous formulation of Glucopyranosyl Lipid A (GLA-AF). Intramuscular injections of study vaccine were administered on days 0, 56, and 112.ResultsNa-APR-1(M74)/Alhydrogel was well-tolerated; the most frequent adverse events were mild or moderate injection site tenderness and pain, and mild or moderate nausea and headache. No serious adverse events or adverse events of special interest related to vaccination were observed. Significantly higher levels of antigen-specific IgG antibodies were induced in those who received 100 µg Na-APR-1(M74) than those who received 30 µg of antigen. Adding GLA-AF to Na-APR-1(M74)/Alhydrogel resulted in higher levels of IgG against Na-APR-1(M74) in both the 30 and 100 µg Na-APR-1(M74) groups in comparison to the non-GLA formulations at the same antigen dose.ConclusionsVaccination of hookworm-naïve adults with recombinant Na-APR-1(M74) was well-tolerated, safe, and induced significant IgG responses against the vaccine antigen Na-APR-1(M74). Given these favorable results, clinical trials of this product were initiated in hookworm-endemic areas of Gabon and Brazil.

Dataset Information

Controlled Human Hookworm Infection: Accelerating Human Hookworm Vaccine Development.

Publications

Controlled Human Hookworm Infection: Accelerating Human Hookworm Vaccine Development.

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